The present invention relates to a novel tricyclic compound and a pharmaceutical composition for use as an immunosuppressant, an anti-allergic agent or a suppressant of the IgE production comprising the same.
A serious problem of a transplantation of a tissue or an organ which is frequently performed in recent years is a rejection symptom for excluding a transplanted part after an operation. Prevention of the rejection symptom is very important for a success of the transplantation.
Various immunosuppressants such as azathioprine, corticoid, Cyclosporin A, Tacrolimus and the like are developed and come into practical use for prevention and a treatment of a rejection symptom against a transplantation of an organ or a tissue or a graft-versus-host reaction which is caused by a bone marrow transplantation. But they are not so satisfactory in view of their effects and side effects.
Allergic diseases such as atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis and the like tend to globally increase in recent years and become serious problems. The conventional antiinflammatory agents are suppressants of releasing chemical mediators from mast cells, receptor inhibitors of the released chemical mediators, suppressants of allergic inflammation response or the like. All of these are agents for symptomatic therapy and are not fundamental therapeutic agents for allergic diseases.
Therefore, the development of a more effective and safer medicinal agent has been expected.
The compounds having a similar structure to a compound of the present invention and exhibiting an immunosuppressive or anti-allergic effect are described in WO94/27980, WO95/13067, WO96/40659, WO96/40143, WO96/38412, WO97/24356, WO97/24324, WO97/46524, JP-A 8-3163, JP-A 9-12457, JP-A 9-71564, JP-A 9-124571 and the like. The liquid crystal compounds are described in JP-A 9-87253, JP-A 63-253065, JP-A 1-106864, JP-A 1-106871, JP-A 2-83346, JP-A 9-48760, JP-A 9-31063 and the like, the compounds exhibiting an insecticide or acaricide activity are described in JP-A 8-193067 and the compounds having a therapeutic activity for circulatory system or psychopathy diseases are described in EP0600717 A1, all of which have a similar structure to a compound of the present invention.
The present invention provides a compound of the formula (I):

 
wherein A ring, B ring and C ring are each independently optionally substituted aromatic carbocycle or optionally substituted 5- or 6-membered heterocycle which may fuse with benzene ring,
W1, W2 and/or W3 represents a bond when A ring, B ring and/or C ring is optionally substituted 5-membered heterocycle,
X is xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl, lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl or xe2x80x94S(O)pxe2x80x94 wherein p is an integer of 0 to 2,
Y is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle,
Y may be optionally substituted lower alkoxy when X is xe2x80x94CH2xe2x80x94,
Y may be optionally substituted lower alkoxycarbonyl; optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94, one of V1 and V2 is a bond and the other is a bond, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94, xe2x80x94CH(OR2)xe2x80x94 wherein R2 is hydrogen or lower alkyl, xe2x80x94COxe2x80x94 or xe2x80x94NHCHR3xe2x80x94 wherein R3 is hydrogen or hydroxy, and
at least one of A ring, B ring and C ring is optionally substituted aromatic carbocycle and at least another one is optionally substituted 5- or 6-membered heterocycle which may fuse with benzene ring when both of V1 and V2 are single bonds,
pharmaceutically acceptable salt or hydrate thereof
The present invention provides a pharmaceutical composition for use as an immunosuppressant, an anti-allergic agent or a suppressant of the IgE production comprising the compound (I), pharmaceutically acceptable salt or hydrate thereof.
In one of the other embodiments, the present invention provides a method for suppressing an immune response or a method for treating and/or preventing allergic diseases comprising administering the compound (I). In another embodiment, the present invention provides use of the compound (I) for manufacturing a medicament for suppressing an immune response or treating and/or preventing allergic diseases.
In the present specification, the term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine. Fluorine or chlorine is preferable.
The term xe2x80x9clower alkylxe2x80x9d includes straight or branched chain alkyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. For example, included are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like.
As substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d, exemplified are halogen; hydroxy; lower alkoxy optionally substituted with lower alkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; mercapt; lower alkylthio; amino optionally substituted with hydroxy, lower alkyl or optionally substituted acyl; imino optionally substituted with hydroxy, lower alkoxy, carboxy(lower)alkoxy, aryl(lower)alkoxy or 5- or 6-membered heterocycle; hydrazono optionally substituted with carbamoyl or lower alkoxycarbonyl; carbamoyl optionally substituted with lower alkyl or amino; thiocarbamoyl optionally substituted with lower alkyl; cycloalkyl optionally substituted with lower alkyl or lower alkoxy; cycloalkenyl optionally substituted with lower alkyl; cyano; phenyl optionally substituted with at least one substituent selected from the group of hydroxy, lower alkyl, carboxy, lower alkoxycarbonyl and lower alkoxy; 5- or 6-membered heterocycle which may be substituted with lower alkyl and may fuse with benzene ring; and the like. The lower alkyl may be substituted with one or more of these substituents at any possible positions. Halogen; hydroxy; acyloxy; phenyl optionally substituted with lower alkyl or lower alkoxy; pyridyl or the like is preferable.
The part of lower alkyl in xe2x80x9clower alkoxyxe2x80x9d is the same as the above xe2x80x9clower alkylxe2x80x9d.
As substituents for xe2x80x9coptionally substituted lower alkoxyxe2x80x9d, exemplified are halogen; hydroxy; lower alkoxy optionally substituted with acyloxy; acyl; acyloxy optionally substituted with hydroxy or carboxy; carboxy; lower alkoxycarbonyl; lower alkylthio; amino optionally substituted with lower alkyl; phenyl optionally substituted with lower alkyl or lower alkoxy; heterocycle; heterocyclylcarbonyloxy and the like.
The parts of lower alkyl in xe2x80x9clower alkoxycarbonylxe2x80x9d, xe2x80x9clower alkylsulfonylxe2x80x9d, xe2x80x9clower alkylsulfonyloxyxe2x80x9d, xe2x80x9clower alkylthioxe2x80x9d, xe2x80x9clower alkylaminoxe2x80x9d and xe2x80x9clower alkylenedioxyxe2x80x9d are the same as the above xe2x80x9clower alkylxe2x80x9d. Substituents for xe2x80x9coptionally substituted lower alkoxycarbonylxe2x80x9d, xe2x80x9coptionally substituted lower alkylsulfonylxe2x80x9d and xe2x80x9coptionally substituted lower alkylthioxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted lower alkoxyxe2x80x9d.
The term xe2x80x9clower alkenylxe2x80x9d includes straight or branched chain alkenyl of 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms more preferably 3 to 6 carbon atoms having at least one double bond at any possible positions. For example, included are vinyl, propenyl such as 2-propenyl and the like, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like. Substituents for xe2x80x9coptionally substituted lower alkenylxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted lower alkoxyxe2x80x9d and alkenyl substituted with halogen or unsubstituted alkenyl is preferable.
The parts of lower alkenyl in xe2x80x9clower alkenyloxyxe2x80x9d, xe2x80x9clower alkenyloxycarbonylxe2x80x9d and xe2x80x9clower alkenylaminoxe2x80x9d are the same as the above xe2x80x9clower alkenylxe2x80x9d. Substituents for xe2x80x9coptionally substituted lower alkenyloxyxe2x80x9d, xe2x80x9coptionally substituted lower alkenyloxycarbonylxe2x80x9d and xe2x80x9coptionally substituted lower alkenylthioxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted lower alkoxyxe2x80x9d.
The term xe2x80x9clower alkynylxe2x80x9d includes straight or branched chain alkynyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms and is exemplified by ethynyl, propynyl such as 2-propynyl, butynyl such as 2-butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These have at least one triple bond and may have some double bonds at any possible positions. Substituents for xe2x80x9coptionally substituted lower alkynylxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted lower alkoxyxe2x80x9d.
The term xe2x80x9cacylxe2x80x9d includes straight or branched chain aliphatic acyl having 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, cyclic aliphatic acyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms and aroyl. For example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl, benzoyl and the like are included. Substituents for xe2x80x9coptionally substituted acylxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted lower alkoxyxe2x80x9d and aroyl may further be substituted with lower alkyl. Among the substituents, halogen is preferable.
The part of acyl in xe2x80x9cacyloxyxe2x80x9d is the same as the above xe2x80x9cacylxe2x80x9d and substituents for xe2x80x9coptionally substituted acyloxyxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted acylxe2x80x9d.
The term xe2x80x9clower alkylcarbonylxe2x80x9d includes aliphatic acyl having 2 to 4 carbon atoms and included are acetyl, propyl, butyryl, isobutyryl and the like. Acetyl is preferable.
The term xe2x80x9ccycloalkylxe2x80x9d includes carbocycle having 3 to 6 carbon atoms and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. As substituents for xe2x80x9coptionally substituted cycloalkylxe2x80x9d exemplified are lower alkyl, halogen, hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxy, lower alkylenedioxy, imino optionally substituted with lower alkoxy, aryl, 5- or 6-membered heterocycle and the like and the cycloalkyl may be substituted at any possible positions.
The term xe2x80x9ccycloalkenylxe2x80x9d includes the group having at least one double bond at any possible positions in the above cycloalkyl and is exemplified by cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl and the like. Substituents for xe2x80x9coptionally substituted cycloalkenylxe2x80x9d are the same as those for the above xe2x80x9ccycloalkylxe2x80x9d.
As substituents for xe2x80x9coptionally substituted aminoxe2x80x9d, exemplified are optionally substituted lower alkyl {wherein the substituents are lower alkoxy, cycloalkyl, optionally substituted amino (wherein the substituents are aroyl optionally substituted with acyloxy(lower)alkoxy), optionally substituted aryl (wherein the substituents are lower alkyl, lower alkoxy, carboxy or lower alkoxycarbonyl) or heterocycle}; lower alkenyl; lower alkynyl; cycloalkyl; aryl optionally substituted with lower alkyl, carboxy, acyl, lower alkoxycarbonyl; sulfamoyl optionally substituted with lower alkyl; optionally substituted lower alkoxycarbonyl (the substituents are halogen, acyloxy, acyloxy substituted with hydroxy, acyloxy substituted with carboxy or heterocyclylcarbonyloxy or the like); lower alkylsulfonyl and the like.
The term xe2x80x9coptionally substituted carbamoylxe2x80x9d includes carbamoyl optionally substituted with lower alkyl, lower alkenyl, lower alkynyl or the like.
The term xe2x80x9coptionally substituted sulfamoylxe2x80x9d includes sulfamoyl optionally substituted with lower alkyl, lower alkenyl, lower alkynyl or the like.
The term xe2x80x9caromatic carbocyclexe2x80x9d includes benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, indene ring and the like and benzene ring is preferable.
The term xe2x80x9carylxe2x80x9d includes phenyl, naphthyl, anthryl, phenanthryl, indenyl and the like and phenyl is preferable.
As substituents for xe2x80x9coptionally substituted aromatic carbocyclexe2x80x9d and xe2x80x9coptionally substituted arylxe2x80x9d, exemplified are halogen; hydroxy; lower alkyl optionally substituted with halogen or carboxy; lower alkoxy optionally substituted with halogen, aryl, heteroaryl or lower alkoxy; lower alkenyl; lower alkynyl; cycloalkyl; lower alkenyloxy; lower alkynyloxy; cycloalkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; lower alkenyloxycarbonyl; lower alkylthio; lower alkynylthio; amino optionally substituted with lower alkyl, cycloalkyl(lower)alkyl, heteroaryl(lower)alkyl, lower alkenyl, cycloalkyl, acyl optionally substituted with halogen, lower alkoxycarbonyl, or lower alkylsulfonyl; guanidino; nitro; lower alkylsulfonyl; dihydroxyborane; lower alkylsulfonyloxy optionally substituted with halogen; arylsulfonyl; arylsulfonyloxy; aryl; 5- or 6-membered heterocycle and the like. The aromatic carbocycle and aryl may be substituted with these substituents at one or more of any possible positions. Preferable examples are halogen; hydroxy; lower alkyl optionally substituted with halogen; lower alkoxy optionally substituted with aryl or lower alkoxy; lower alkenyloxy; acyloxy; lower alkylthio; amino optionally substituted with lower alkyl, lower alkenyl, acyl optionally substituted with halogen, or lower alkylsulfonyl; nitro; lower alkylsulfonyl; lower alkylsulfonyloxy optionally substituted with halogen; or arylsulfonyloxy.
The parts of aryl in xe2x80x9carylsulfonylxe2x80x9d and xe2x80x9carylsulfonyloxyxe2x80x9d are the same as the above xe2x80x9carylxe2x80x9d and phenyl is preferable. Substituents for xe2x80x9coptionally substituted arylsulfonylxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted arylxe2x80x9d and unsubstituted arylsulfonyl is preferable.
The term xe2x80x9c5- or 6-membered heterocyclexe2x80x9d includes 5- or 6-membered heterocycle which contains at least one of hetero atoms arbitrarily selected from a group of O, S and N. Examples of heterocycle include aromatic heterocycle such as pyrrole ring, imidazole ring, pyrazole ring, pyridine ring such as 4-pyridyl, pyridazine ring, pyrimidine ring, pyrazine ring, triazole ring, triazine ring, isoxazole ring, oxazole ring, oxadiazole ring, isothiazole ring, thiazole ring, thiadiazole ring, furan ring such as 2-furyl or 3-furyl, thiophene ring such as 3-thienyl and the like, aliphatic heterocycle such as tetrahydropyrane ring, dihydropyridine ring such as 1,2-dihydropyridyl, dihydropyridazine such as 2,3-dihydropyridazinyl, dihydropyrazine ring such as 1,2-dihydropyrazinyl, dioxane ring, oxathiorane ring, thiane ring, pyrrolidine ring, pyrroline ring, imidazolidine ring, imidazoline ring, pyrazolidine ring, pyrazoline ring, piperidine ring, piperazine ring, morpholine ring and the like.
The term xe2x80x9c5- or 6-membered heterocycle which contains one or two hetero atomsxe2x80x9d includes aromatic heterocycle such as pyrrole ring, imidazole ring, pyrazole ring, pyridine ring, pyridazine ring, pyrimicline ring, pyrazine ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, furan ring, thiophene ring or the like and aliphatic heterocycle such as dioxane ring, oxathiorane ring, thiane ring, dihydropyridine ring, pyrrolidine ring, pyrroline ring, imidazolidine ring, imidazoline ring, pyrazolidine ring, pyrazoline ring, piperidine ring, piperazine ring, morpholine ring or the like among the above xe2x80x9c5- or 6-membered heterocyclexe2x80x9d. Aromatic heterocycle is preferable.
As xe2x80x9c5- or 6-membered ring which may fuse with benzene ringxe2x80x9d, exemplified are indole ring, isoindole ring, benzimidazole ring, indazole ring, cinnoline ring, phthalazine ring, quinazoline ring, benzisoxazole ring, benzoxazole ring, benzoxadiazole ring, benzothiazole ring, benzisothiazole ring, benzofuran ring, benzothiophen ring, benzotriazole ring, isobenzofuran ring, chromen ring, indoline ring, isoindoline ring and the like.
As substituents for xe2x80x9coptionally substituted 5- or 6-membered heterocyclexe2x80x9d and xe2x80x9coptionally substituted 5- or 6-membered heterocycle which may fuse with benzene ringxe2x80x9d exemplified are halogen; hydroxy; lower alkyl optionally substituted with hydroxy or acyloxy; lower alkoxy optionally substituted with halogen, aryl or 5- or 6-membered heterocycle; lower alkenyl; lower alkenyloxy; lower alkynyl; lower alkynyloxy; acyloxy; carboxy; lower alkoxycarbonyl; mercapt; lower alkylthio; lower alkenylthio; amino which may be mono- or di-substituted with halogen, optionally substituted lower alkyl wherein the substituents are cycloalkyl or 5- or 6-membered heterocycle, acyl optionally substituted with halogen, lower alkenyl, cycloalkyl, or lower alkylsulfonyl; imino optionally substituted with lower alkylsulfonyl; nitro; lower alkylsulfonyl; aryl; 5- or 6-membered heterocycle; oxo; oxide and the like. These substituents may substitute at one or more of any possible positions.
The substituents for xe2x80x9coptionally substituted 5- or 6-membered heterocycle which contains one or two of hetero atomsxe2x80x9d are the same as the above. 5- or 6-membered heterocycle substituted with lower alkyl or unsubstituted one is preferable.
The term xe2x80x9cW1, W2 and/or W3 represents a bond when A ring, B ring and/or C ring is optionally substituted 5-membered heterocyclexe2x80x9d means as follows: W1 represents a bond when A ring is optionally substituted 5-membered heterocycle, resulting in the binding positions of V1 and X to A ring as shown below.

 
Each of W2 and W3 represents a bond when B ring or C ring is 5-membered heterocycle, resulting in the binding positions of V1 and V2 shown below.

 
Each of X, V1 and V2 may directly bind to a hetero atom constituting A ring, B ring or C ring.
The term xe2x80x9ccompound (I)xe2x80x9d includes formable and pharmaceutically acceptable salts of each compound. As xe2x80x9cthe pharmaceutically acceptable saltxe2x80x9d, exemplified are salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid and the like; salts with organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid and the like; salts with organic base such as ammonium, trimethylammonium, triethylammonium and the like; salts with alkaline metals such as sodium, potassium and the like and salts with alkaline earth metals such as calcium, magnesium and the like.
The compound of the present invention includes hydrates and all of stereoisomers, for example, atropisomers etc. thereof.
All of the compounds (I) have an immunosuppressive effect, an anti-allergic effect and/or a suppressive effect on the IgE production and the following compounds are specifically preferable.
In the formula (I),
1) a compound wherein A ring is optionally substituted benzene ring,
preferably A ring is optionally substituted benzene ring {wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy, acyloxy, lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy (wherein the substituents are halogen) or arylsulfonyloxy},
more preferably A ring is optionally substituted benzene ring (wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy or lower alkylsulfonyloxy),
2) a compound wherein B ring is optionally substituted benzene ring, optionally substituted pyridine ring, optionally substituted pyrimidine ring, optionally substituted pyridazine ring, optionally substituted pyrazine ring, optionally substituted thiophene ring, optionally substituted furan ring, optionally substituted pyrazole ring or optionally substituted oxazole ring,
preferably B ring is optionally substituted benzene ring (wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, cycloalkoxy, lower alkoxycarbonyl or lower alkylsulfonyloxy), optionally substituted pyridine ring (wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkenyl, amino, carboxy or lower alkoxycarbonyl),
optionally substituted pyrimidine ring {wherein the substituents are halogen, optionally substituted lower alkyl (wherein the substituents are hydroxy or acyloxy), lower alkoxy, lower alkylthio, optionally substituted amino (wherein the substituents are lower alkyl), carboxy or lower alkoxycarbonyl},
optionally substituted pyridazine ring (wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkenyl, amino, carboxy, lower alkoxycarbonyl or oxide),
optionally substituted thiophene ring (wherein the substituents are lower alkyl), optionally substituted pyrazole ring {wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy), lower alkoxy, carboxy or lower alkoxycarbonyl},
or optionally substituted oxazole ring (wherein the substituents are lower alkyl), more preferably B ring is optionally substituted benzene ring (wherein the substituents are hydroxy, lower alkyl, lower alkoxy or lower alkylsulfonyloxy), optionally substituted pyridine ring wherein the substituents are halogen or lower alkyl),
optionally substituted pyrimidine ring {wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy or acyloxy), lower alkoxy, lower alkylthio, optionally substituted amino (wherein the substituents are lower alkyl), carboxy or lower alkoxycarbonyl},
optionally substituted pyrazole ring {wherein the substituents are optionally substituted lower alkyl(wherein the substituents are hydroxy), lower alkoxy, carboxy or lower alkoxycarbonyl},
3) a compound wherein C ring is optionally substituted benzene ring, optionally substituted pyridine ring, optionally substituted pyrimidine ring, optionally substituted pyridazine ring, optionally substituted pyrazine ring, optionally substituted isoxazole ring, optionally substituted pyrazole ring, optionally substituted benzothiazole ring, optionally substituted morpholine ring, optionally substituted piperazine ring, optionally substituted imidazole ring, optionally substituted triazole ring, optionally substituted dihydropyridine ring, optionally substituted dihydropyridazine ring or optionally substituted dihydropyrazine ring, preferably C ring is optionally substituted benzene ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkyl (wherein the substituents are halogen), optionally substituted lower alkoxy (wherein the substituents are aryl or lower alkoxy), lower alkenyloxy, lower alkylthio, optionally substituted amino {wherein the substituents are lower alkyl, lower alkenyl, optionally substituted acyl (wherein the substituents are halogen) or lower alkylsulfonyl], nitro, lower alkylsulfonyl or lower alkylsulfonyloxy},
optionally substituted pyridine ring, optionally substituted pyrimidine ring, optionally substituted pyridazine ring, optionally substituted pyrazine ring, optionally substituted isoxazole ring, optionally substituted pyrazole ring (wherein the substituents are halogen, hydroxy, optionally substituted lower alkyl (wherein the substituents are hydroxy or acyloxy), optionally substituted lower alkoxy (wherein the substituents are halogen, aryl or 5- or 6-membered heterocycle), lower alkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, acyloxy, carboxy, lower alkoxycarbonyl, mercapt, lower alkylthio, lower alkenylthio, optionally mono- or di-substituted amino {wherein the substituents are halogen, optionally substituted lower alkyl (wherein the substituents are cycloalkyl or 5- or 6-membered heterocycle), optionally substituted acyl (wherein the substituents are halogen), lower alkenyl, cycloalkyl or lower alkylsulfonyl}, optionally substituted imino (wherein the substituents are lower alkylsulfonyl), nitro, lower alkylsulfonyl, aryl, 5- or 6-membered heterocycle, oxo or oxide},
benzothiazole ring,
optionally substituted dihydropyridine (wherein the substituents are oxo), optionally substituted dihydropyridazine ring (wherein the substituents are oxo), optionally substituted dihydropyrazine ring (wherein the substituents are oxo), more preferably C ring is optionally substituted benzene ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkyl (wherein the substituents are halogen), optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, lower alkylthio, optionally mono- or di-substituted amino {wherein the substituents are lower alkyl, lower alkenyl, optionally substituted acyl (wherein the substituents are halogen) or lower alkylsulfonyl], nitro, lower alkylsulfonyl or lower alkylsulfonyloxy},
optionally substituted pyridine ring {wherein the substituents are halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, optionally substituted lower alkoxy (wherein the substituents are halogen, aryl or 5- or 6-membered heterocycle), lower alkenyloxy, lower alkynyloxy, lower alkylthio, lower alkenylthio, optionally substituted amino (wherein the substituents are lower alkyl, heterocyclyl(lower)alkyl, cycloalkylalkyl, lower alkenyl or cycloalkyl), lower alkylsulfonyl, 5- or 6-membered heterocycle, nitro or oxo},
optionally substituted pyrimidine ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, or optionally substituted amino (wherein the substituents are lower alkyl or lower alkenyl)},
optionally substituted pyridazine ring {wherein the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, or optionally substituted amino (wherein the substituents are lower alkyl, lower alkoxy or lower alkenyl)},
optionally substituted pyrazine ring {wherein the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkenyl)},
4) a compound wherein X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94 (wherein R1 is hydrogen, methyl or prenyl), preferably X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NMexe2x80x94,
more preferably X is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94,
5) a compound wherein Y is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, lower alkylsulfonyl or optionally substituted acyl, preferably Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, lower alkylsulfonyl or optionally substituted acyl,
more preferably Y is optionally substituted lower alkyl {wherein the substituents are 5- or 6-membered heterocycle, or optionally substituted phenyl (wherein the substituents are lower alkyl or lower alkoxy)} or optionally substituted lower alkenyl (wherein the substituents are halogen),
most preferably Y is methyl, optionally substituted prenyl (wherein the substituents are halogen) or optionally substituted benzyl (wherein the substituents are lower alkyl or lower alkoxy),
6) a compound wherein X is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and Y is optionally substituted prenyl (wherein the substituents are halogen), or optionally substituted benzyl(wherein the substituents are lower alkyl or lower alkoxy), or X is xe2x80x94NR1 and Y is methyl, preferably xe2x80x94Xxe2x80x94Y is xe2x80x94OCH2CHxe2x95x90CMe2, xe2x80x94OBn, xe2x80x94OCH2C6H4-2-Me, xe2x80x94OCH2C6H4-3-Me, xe2x80x94OCH2C6H4-4-Me, xe2x80x94OCH2C6H4-4-OMe, xe2x80x94NMe2 or xe2x80x94NHCH2CHxe2x95x90CMe2, more preferably xe2x80x94Xxe2x80x94Y is xe2x80x94OCH2CHxe2x95x90CMe2, xe2x80x94OBn or xe2x80x94NMe2,
7) a compound wherein one of V1 and V2 is a single bond and the other is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94,
preferably V1 is a single bond and V2 is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, more preferably both of V1 and V2 are single bonds,
8) a compound wherein A ring is optionally substituted benzene ring,
B ring is optionally substituted benzene ring, optionally substituted pyridine ring, optionally substituted pyrimidine ring, optionally substituted pyridazine ring, optionally substituted pyrazine ring, optionally substituted thiophene ring, optionally substituted furan ring, optionally substituted pyrazole ring or optionally substituted oxazole ring,
C ring is optionally substituted benzene ring, optionally substituted pyridine ring, optionally substituted pyrimidine ring, optionally substituted pyridazine ring, optionally substituted pyrazine ring, optionally substituted isoxazole ring, optionally substituted pyrazole ring, optionally substituted benzothiazole ring, optionally substituted morpholine ring, optionally substituted piperazine ring, optionally substituted imidazole ring or optionally substituted triazole ring,
X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, methyl or prenyl,
Y is optionally substituted lower alkyl or optionally substituted lower alkenyl, and one of V1 and V2 is a single bond and the other is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, preferably A ring is optionally substituted benzene ring {wherein the substituents are halogen, hydroxy, lower alkoxy, acyloxy, lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy (wherein the substituents are halogen) or arylsulfonyloxy},
B ring is optionally substituted benzene ring (wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkenyloxy or lower alkylsulfonyloxy),
optionally substituted pyridine ring (wherein the substituents are halogen or lower alkyl),
optionally substituted pyrimidine ring {wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy or acyloxy), lower alkoxy, lower alkylthio, optionally substituted amino (wherein the substituents are lower alkyl), carboxy or lower alkoxycarbonyl)},
optionally substituted pyridazine ring (wherein the substituents are lower alkyl or oxide),
optionally substituted thiophene ring (wherein the substituents are lower alkyl), optionally substituted pyrazole ring {wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy), lower alkoxy, carboxy, or lower alkoxycarbonyl},
or optionally substituted oxazole ring (wherein the substituents are lower alkyl),
C ring is optionally substituted benzene ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkyl (wherein the substituents are halogen), optionally substituted lower alkoxy (wherein the substituents are aryl or lower alkoxy), lower alkenyloxy, lower alkylthio, optionally substituted amino {wherein the substituents are lower alkyl, lower alkenyl, optionally substituted acyl (wherein the substituents are halogen) or lower alkylsulfonyl}, nitro, lower alkylsulfonyl or lower alkylsulfonyloxy},
optionally substituted pyridine ring {wherein the substituents are halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, optionally substituted lower alkoxy (wherein the substituents are halogen, aryl or 5- or 6-membered heterocycle), lower alkenyloxy, lower alkynyloxy, lower alkylthio, lower alkenylthio, optionally substituted amino (wherein the substituents are lower alkyl, heterocyclyl(lower)alkyl, cycloalkylalkyl, lower alkenyl or cycloalkyl), lower alkylsulfonyl, 5- or 6-membered heterocycle, nitro or oxo},
optionally substituted pyrimidine ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl or lower alkenyl)},
optionally substituted pyridazine ring {wherein the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl, lower alkoxy or lower alkenyl)},
optionally substituted pyrazine ring {the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, optionally substituted amino (wherein the substituents are lower alkenyl)},
optionally substituted isoxazole ring {wherein the substituents are optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, or optionally substituted amino (wherein the substituents are lower alkenyl or lower alkylsulfonyl)},
optionally substituted pyrazole ring {wherein the substituents are lower alkyl, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, or optionally substituted amino (wherein the substituents are lower alkenyl or lower alkylsulfonyl)},
or benzothiazole ring,
X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NMexe2x80x94,
Y is optionally substituted lower alkyl {wherein the substituents are 5- or 6-membered heterocycle or optionally substituted phenyl (wherein the substituents are lower alkyl or lower alkoxy)} or lower alkenyl (wherein the substituents are halogen), and one of V1 and V2 is a single bond and the other is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, more preferably A ring is optionally substituted benzene ring (wherein the substituents are halogen, hydroxy, lower alkoxy or lower alkylsulfonyloxy),
B ring is benzene ring (wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl),
optionally substituted pyridine ring (wherein the substituents are halogen or lower alkyl),
optionally substituted pyrimidine ring {wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy or acyloxy), lower alkoxy, lower alkylthio, optionally substituted amino (wherein the substituents are lower alkyl), carboxy or lower alkoxycarbonyl},
optionally substituted pyrazole ring {wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy), lower alkoxy, carboxy, or lower alkoxycarbonyl},
C ring is optionally substituted benzene ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkyl (wherein the substituents are halogen), optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, lower alkylthio, optionally substituted amino {wherein the substituents are lower alkyl, lower alkenyl, optionally substituted acyl (wherein the substituents are halogen), or lower alkylsulfonyl}, nitro, lower alkylsulfonyl or lower alkylsulfonyloxy},
optionally substituted pyridine ring {wherein the substituents are halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, optionally substituted lower alkoxy (wherein the substituents are halogen, aryl or 5- or 6-membered heterocycle), lower alkenyloxy, lower alkynyloxy, lower alkylthio, lower alkenylthio, optionally substituted amino (wherein the substituents are lower alkyl, heterocyclyl(lower)alkyl, cycloalkylalkyl, lower alkenyl or cycloalkyl), lower alkylsulfonyl, 5- or 6-membered heterocycle, nitro or oxo},
optionally substituted pyrimidine ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl or lower alkenyl)},
optionally substituted pyridazine ring {wherein the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl, lower alkoxy or lower alkenyl)},
or optionally substituted pyrazine ring {wherein the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkenyl)},
X is xe2x80x94Oxe2x80x94 and Y is prenyl or optionally substituted benzyl (wherein the substituents are lower alkyl or lower alkoxy) or X is xe2x80x94NR1xe2x80x94 and Y is methyl.
V1 is a single bond and V2 is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, more preferably A ring is optionally substituted benzene ring (wherein the substituents are halogen, hydroxy, lower alkoxy or lower alkylsulfonyloxy),
B ring is optionally substituted benzene ring (wherein the substituents are halogen, hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl), optionally substituted pyridine ring (wherein the substituents are lower alkyl),
optionally substituted pyrimidine ring (wherein the substituents are lower alkyl, lower alkoxy, carboxy or lower alkoxycarbonyl),
optionally substituted pyrazole ring (wherein the substituents are lower alkyl, lower alkoxy, carboxy or lower alkoxycarbonyl),
C ring is optionally substituted benzene ring {wherein the substituents are halogen, hydroxy, lower alkoxy, lower alkenyloxy, optionally substituted amino (wherein the substituents are lower alkyl) or lower alkylsulfonyloxy},
optionally substituted pyridine ring {wherein the substituents are optionally substituted amino {wherein the substituents are halogen, lower alkyl, optionally substituted lower alkoxy (wherein the substituents are aryl or 5- or 6-membered heterocycle), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl, heterocyclyl(lower)alkyl or lower alkenyl)},
optionally substituted pyrimidine ring (wherein the substituents are halogen, hydroxy, lower alkoxy, lower alkenyloxy, amino or lower alkenylamino), optionally substituted pyridazine ring (wherein the substituents are halogen, lower alkoxy, lower alkenyloxy, amino, lower alkylamino or lower alkenylamino), or optionally substituted pyrazine ring (wherein the substituents are lower alkenyloxy, amino or lower alkenylamino),
X is xe2x80x94Oxe2x80x94 and Y is prenyl or optionally substituted benzyl (wherein the substituents are lower alkyl or lower alkoxy) or X is NR1 and Y is methyl or prenyl,
V1 is a single bond and V2 is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NH,
9) a compound wherein two of A ring, B ring and C ring are optionally substituted benzene ring and the other one is optionally substituted 5- or 6-membered heterocycle which may fuse with benzene ring,
preferably A ring is optionally substituted benzene ring, one of B ring and C ring is optionally substituted benzene ring and the other is optionally substituted 5- or 6-membered heterocycle which may fuse with benzene ring,
more preferably A ring is optionally substituted benzene ring, one of B ring and C ring is optionally substituted benzene ring and the other is optionally substituted 5- or 6-membered heterocycle which may fuse with benzene ring and both of V1 and V2 are single bonds,
10) a compound wherein all of A ring, B ring and C ring are optionally substituted benzene ring, V1 is a single bond and V2 is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94,
11) a compound wherein both of A ring and B ring are optionally substituted benzene ring and xe2x80x94Xxe2x80x94Y is xe2x80x94NMe2, prenyloxy or prenylamino,
preferably both of A ring and B ring are optionally substituted benzene ring and C ring is optionally substituted pyridine ring, optionally substituted pyrimidine ring,
optionally substituted pyridazine ring, optionally substituted isoxazole ring or optionally substituted pyrazole ring, xe2x80x94Xxe2x80x94Y is xe2x80x94NMe2, prenyloxy or prenylamino and both of V1 and V2 are single bonds,
12) a compound of any of following formulas

 
wherein R4, R5, R6 and R7 are each independently hydrogen, halogen, hydroxy, lower alkoxy, acyloxy, optionally substituted lower alkylsulfonyloxy (wherein the substituents are halogen) or arylsulfonyloxy,
R8, R9, R10 and R11 are each independently hydrogen, hydroxy, lower alkyl, lower alkoxy or lower alkylsulfonyloxy,
R12, R13, R14, R15 and R16 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl(wherein the substituents are halogen), optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, nitro or optionally substituted amino {wherein the substituents are lower alkyl, lower alkenyl, optionally substituted acyl (wherein the substituents are halogen) or lower alkylsulfonyl},
B ring is optionally substituted pyridine ring (wherein the substituents are halogen or lower alkyl),
optionally substituted pyrimidine ring {wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy or acyloxy), lower alkoxy, lower alkylthio, optionally substituted amino (wherein the substituents are lower alkyl), carboxy or lower alkoxycarbonyl},
optionally substituted pyridazine (wherein the substituents are lower alkyl or oxide), optionally substituted thiophene ring (wherein the substituents are lower alkyl),
optionally substituted pyrazole ring (wherein the substituents are optionally substituted lower alkyl (wherein the substituents are hydroxy), lower alkoxy, carboxy or lower alkoxycarbonyl},
or optionally substituted oxazole ring (wherein the substituents are lower alkyl),
C ring is optionally substituted pyridine ring {wherein the substituents are hydroxy, halogen, lower alkyl, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy, optionally substituted amino (wherein the substituents are lower alkyl, optionally substituted acyl (wherein the substituents are halogen), lower alkenyl, or lower alkylsulfonyl}, nitro, lower alkylthio, lower alkylsulfonyl or optionally substituted imino (wherein the substituents are lower alkylsulfonyl)},
optionally substituted pyrimidine ring {wherein the substituents are halogen, hydroxy, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl or lower alkenyl)},
optionally substituted pyridazine ring {wherein the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl, lower alkoxy, lower alkenyl or lower alkenyloxy)},
optionally substituted pyrazine ring {wherein the substituents are halogen, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkyl or lower alkenyl)},
optionally substituted isoxazole ring {wherein the substituents are optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkenyl or lower alkylsulfonyl)},
optionally substituted pyrazole ring {wherein the substituents are lower alkyl, optionally substituted lower alkoxy (wherein the substituents are aryl), lower alkenyloxy or optionally substituted amino (wherein the substituents are lower alkenyl or lower alkylsulfonyl)},
benzothiazole ring,
morpholine ring,
piperazine ring (wherein the substituents are lower alkyl or phenyl),
imidazole ring or triazole ring,
V1 is a single bond or xe2x80x94Oxe2x80x94,
V2 is a single bond, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94, xe2x80x94CH(OEt)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NHCH2xe2x80x94 or xe2x80x94NHCH(OH)xe2x80x94,
X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94 (wherein R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl, lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl), and Y is methyl, optionally substituted prenyl (wherein the substituents are halogen) or optionally substituted benzyl (wherein the substituents are lower alkyl or lower alkoxy)
13) a compound wherein both of A ring and B ring are optionally substituted benzene ring and C ring is

 
Y is CH2CHxe2x95x90CMe2 and both of V1 and V2 are single bonds,
14) a compound wherein both of A ring and B ring are benzene ring, C ring is

 
X is xe2x80x94Oxe2x80x94, Y is hydrogen, and both of V1 and V2 are single bonds,
15) a compound wherein both of A ring and B ring is optionally substituted benzene ring, C ring is

 
X is xe2x80x94NHxe2x80x94 and both of V1 and V2 are single bonds.
Another preferable embodiment is,
[1] a compound of the following formula (Ibxe2x80x2):

 
wherein C ring is optionally substituted 5- or 6-membered heterocycle which contains one or two hetero atoms and W3 represents a bond when C ring is 5-membered heterocycle,
X and Xxe2x80x2 are each independently xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl, lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl, or xe2x80x94S(O)pxe2x80x94 wherein p is an integer of 0-2,
Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle,
R1, taken together with Y or Yxe2x80x2, may form xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)2xe2x80x94Qxe2x80x94(CH2)2xe2x80x94 wherein Q is CH2, O, S or NRxe2x80x2, xe2x80x94CRxe2x80x2xe2x95x90CHxe2x80x94CHxe2x95x90CRxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94O(CH2)nxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94(CH2)nxe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94Nxe2x95x90CHxe2x80x94 wherein m is 4 or 5, n is 2 or 3,
Rxe2x80x2 is hydrogen, lower alkyl or lower alkenyl,
Y may be optionally substituted lower alkoxy when X is xe2x80x94CH2xe2x80x94, Yxe2x80x2 may be optionally substituted lower alkoxy when Xxe2x80x2 is xe2x80x94CH2xe2x80x94,
Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or NR1,
Yxe2x80x2 may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when Xxe2x80x2 is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94,
Y may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or NR1xe2x80x94,
Yxe2x80x2 may be hydrogen or halogen when Xxe2x80x2 is xe2x80x94CH2xe2x80x94 or xe2x80x94NR1xe2x80x94.
R4, R5, R6, R7, R8, R9, R10 and R11 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted cycloalkyloxy, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkenyloxycarbonyl, optionally substituted lower alkylthio, optionally substituted lower alkenylthio, optionally substituted amino, optionally substituted carbamoyl, guanidino, nitro, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyl or optionally substituted arylsulfonyloxy,
excluding compounds wherein all of R8, R9, R10 and R11 are selected from hydrogen and halogen.
In the following compound of the formula (Ibxe2x80x2), preferable is:
a compound wherein R4 and R5 are each independently hydrogen, hydroxy, halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyloxy, optionally substituted lower alkylsulfonyloxy or optionally substituted arylsulfonyloxy (hereinafter referred to as xe2x80x9cR4 and R5 are R45-1xe2x80x9d),
a compound wherein R4 and R5 are each independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, acyloxy, optionally substituted lower alkylsulfonyloxy or arylsulfonyloxy (hereinafter referred to as xe2x80x9cR4 and R5 are R45-2xe2x80x9d),
a compound wherein R4 and R5 are each independently hydrogen, halogen or lower alkoxy (hereinafter referred to as xe2x80x9cR4 and R5 are R45-3xe2x80x9d),
a compound wherein one of R4 and R5 is hydrogen and the other is halogen (hereinafter referred to as xe2x80x9cR4 and R5 are R45-4xe2x80x9d),
a compound wherein one of R4 and R5 is hydrogen and the other is chloro or fluoro (hereinafter referred to as xe2x80x9cR4 and R5 are R45-5xe2x80x9d),
a compound wherein R4 is hydrogen and R5 is halogen (hereinafter referred to as xe2x80x9cR4 and R5 are R45-6xe2x80x9d),
a compound wherein R4 is hydrogen and R5 is chloro or fluoro (hereinafter referred to as xe2x80x9cR4 and R5 are R45-7xe2x80x9d),
a compound wherein R6 and R7 are each independently hydrogen, halogen or lower alkyl (hereinafter referred to as xe2x80x9cR6 and R7 are R67-1xe2x80x9d),
a compound wherein both of R6 and R7 are hydrogen (hereinafter referred to as xe2x80x9cR6 and R7 are R67-2xe2x80x9d),
a compound wherein R8 and R11 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkoxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl or optionally substituted lower alkylsulfonyloxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-1xe2x80x9d),
compound wherein R8 and R11 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkoxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl or optionally substituted lower alkylsulfonyloxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-2xe2x80x9d),
a compound wherein R8 and R11 are each independently hydrogen, halogen hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted lower alkoxycarbonyl (hereinafter referred to as xe2x80x9cR8 and R11 are R811-3xe2x80x9d),
a compound wherein R8 and R11 are each independently hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy or lower alkoxycarbonyl (hereinafter referred to as xe2x80x9cR8 and R11 are R811-4xe2x80x9d),
a compound wherein R8 and R11 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy or lower alkoxycarbonyl (hereinafter referred to as xe2x80x9cR8 and R11 are R811-5xe2x80x9d),
a compound wherein R8 and R11 are each independently hydrogen, optionally substituted lower alkyl or optionally substituted lower alkoxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-6xe2x80x9d),
a compound wherein R8 and R11 are each independently optionally substituted lower alkyl or optionally substituted lower alkoxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-7xe2x80x9d),
a compound wherein R8 and R11 are each independently lower alkyl or lower alkoxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-8xe2x80x9d),
a compound wherein both of R8 and R11 are optionally substituted lower alkyl or optionally substituted lower alkoxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-9xe2x80x9d),
a compound wherein both of R8 and R11 are lower alkyl, or one of R8 and R11 is lower alkyl and the other is lower alkoxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-10xe2x80x9d),
a compound wherein both of R8 and R11 are lower alkyl (hereinafter referred to as xe2x80x9cR8 and R11 are R811-11xe2x80x9d),
a compound wherein R8 and R11 are each independently methyl or methoxy (hereinafter referred to as xe2x80x9cR8 and R11 are R811-12xe2x80x9d),
a compound wherein R9 and R10 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkoxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl or optionally substituted lower alkylsulfonyloxy (hereinafter referred to as xe2x80x9cR9 and R10 are R910-1xe2x80x9d),
a compound wherein R9 and R10 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, cycloalkoxy, lower alkylthio, lower alkoxycarbonyl or optionally substituted lower alkylsulfonyloxy (hereinafter referred to as xe2x80x9cR9 and R10 are R910-2xe2x80x9d),
a compound wherein R9 and R10 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted lower alkylsulfonyloxy (hereinafter referred to as xe2x80x9cR9 and R10 are R910-3xe2x80x9d),
a compound wherein R9 and R10 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl or optionally substituted lower alkoxy (hereinafter referred to as xe2x80x9cR9 and R10 are R910-4xe2x80x9d),
a compound wherein R9 and R10 are each independently hydrogen, optionally substituted lower alkyl or optionally substituted lower alkoxy (hereinafter referred to as xe2x80x9cR9 and R10 are R910-5xe2x80x9d),
a compound wherein R9 and R10 are each independently hydrogen or optionally substituted lower alkyl (hereinafter referred to as xe2x80x9cR9 and R10 are R910-6xe2x80x9d),
a compound wherein both of R9 and R10 are hydrogen or optionally substituted lower alkyl (hereinafter referred to as xe2x80x9cR9 and R10 are R910-7xe2x80x9d),
a compound wherein both of R9 and R10 are hydrogen or lower alkyl (hereinafter referred to as xe2x80x9cR9 and R10 are R910-8xe2x80x9d),
a compound wherein both of R9 and R10 are hydrogen (hereinafter referred to as xe2x80x9cR9 and R10 are R910-9xe2x80x9d),
a compound wherein both of R9 and R10 are lower alkyl (hereinafter referred to as xe2x80x9cR9 and R10 are R910-10xe2x80x9d),
a compound wherein R9 and R10 are each independently hydrogen or lower alkyl (hereinafter referred to as xe2x80x9cR9 and R10 are R910-11xe2x80x9d),
a compound wherein C ring is 5- or 6-membered heterocycle which contains at least one N atom (hereinafter referred to as xe2x80x9cC ring is C-1xe2x80x9d),
a compound wherein C ring is a 6-membered heterocycle which contains at least one N atom (hereinafter referred to as xe2x80x9cC ring is C-2xe2x80x9d),
a compound wherein C ring is optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyridazine or optionally substituted pyrazine (hereinafter referred to as xe2x80x9cC ring is C-3xe2x80x9d),
a compound wherein C ring is optionally substituted pyridine or optionally substituted pyrimidine (hereinafter referred to as xe2x80x9cC ring is C-4xe2x80x9d),
a compound wherein C ring is

 
xe2x80x83wherein G1 is CR13 or N, G2 is CR15 or N and R12, R13, R14 and R15 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkenyloxycarbonyl, optionally substituted lower alkylthio, optionally substituted lower alkenylthio, optionally substituted amino, guanidino, nitro, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyl or optionally substituted arylsulfonyloxy (hereinafter referred to as xe2x80x9cC ring is C-5xe2x80x9d),
a compound wherein C ring is

 
xe2x80x83wherein G1 is CR13 or N, G2 is CR15 or N and R12, R13, R14 and R15 are each independently hydrogen, halogen, hydroxy, lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted amino or nitro (hereinafter referred to as xe2x80x9cC ring is C-6xe2x80x9d),
a compound wherein C ring is C-5 and G1 and G2 are each independently CH or N (hereinafter referred to as xe2x80x9cC ring is C-7xe2x80x9d),
a compound wherein C ring is C-6 and G1 and G2 are each independently CH or N (hereinafter referred to as xe2x80x9cC ring is C-8xe2x80x9d),
a compound wherein C ring is

 
xe2x80x83(hereinafter referred to as xe2x80x9cC ring is C-9xe2x80x9d)
a compound wherein X and Xxe2x80x2 are xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR1xe2x80x94 (wherein R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl, lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl) or xe2x80x94S(O)pxe2x80x94 wherein p is an integer of 0-2,
Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted amino, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle,
Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94,
Yxe2x80x2 may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when Xxe2x80x2 is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94,
Y may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or NR1 and Yxe2x80x2 may be hydrogen or halogen when Xxe2x80x2 is xe2x80x94CH2xe2x80x94 or xe2x80x94NR1xe2x80x94 provided that Y and Yxe2x80x2 are not simultaneously hydrogen (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-1xe2x80x9d),
a compound wherein X and Xxe2x80x2 are each independently xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl, lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl or xe2x80x94S(O)pxe2x80x94 wherein p is an integer of 0-2,
Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-2xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl, lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-3xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NHxe2x80x94 (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-4xe2x80x9d),
a compound wherein at least one of Y and Yxe2x80x2 is prenyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-5xe2x80x9d),
a compound wherein X and Xxe2x80x2 are each independently xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, lower alkyl, lower alkenyl or optionally substituted lower alkoxycarbonyl, Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-6xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, lower alkyl, lower alkenyl or optionally substituted lower alkoxycarbonyl, Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-7xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NH, Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-8xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, lower alkyl or lower alkenyl, Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, or optionally substituted lower alkenyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-9xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NHxe2x80x94, Y and Yxe2x80x2 are each independently optionally substituted lower alkyl or optionally substituted lower alkenyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-10xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, lower alkyl, lower alkenyl or optionally substituted lower alkoxycarbonyl, one of Y and Yxe2x80x2 is lower alkyl or lower alkenyl and the other is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-11xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NHxe2x80x94, one of Y and Yxe2x80x2 is lower alkyl or lower alkenyl and the other is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-12xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, lower alkyl, lower alkenyl or optionally substituted lower alkoxycarbonyl, one of Y and Yxe2x80x2 is lower alkyl or lower alkenyl and the other is hydrogen or optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-13xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NHxe2x80x94, one of Y and Yxe2x80x2 is lower alkyl or lower alkenyl and the other is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-14xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, lower alkyl, lower alkenyl or optionally substituted lower alkoxycarbonyl, one of Y and Yxe2x80x2 is prenyl and the other is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-15xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NHxe2x80x94, one of Y and Yxe2x80x2 is prenyl and the other is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted sulfamoyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-16xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NR1xe2x80x94 wherein R1 is hydrogen, lower alkyl, lower alkenyl or optionally substituted lower alkoxycarbonyl, one of Y and Yxe2x80x2 is prenyl and the other is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-17xe2x80x9d),
a compound wherein one of X and Xxe2x80x2 is xe2x80x94Oxe2x80x94 and the other is xe2x80x94NHxe2x80x94, one of Y and Yxe2x80x2 is prenyl and the other is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-18xe2x80x9d),
a compound wherein one of xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is optionally substituted lower alkylamino or optionally substituted lower alkenylamino and the other is optionally substituted lower alkoxy or optionally substituted lower alkenyloxy (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-19xe2x80x9d),
a compound wherein one of xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is optionally substituted lower alkylamino or optionally substituted lower alkenylamino and the other is prenyloxy (hereinafter referred to as xe2x80x9cX, Xxe2x80x2, Y and Yxe2x80x2 are XY-20xe2x80x9d),
a compound wherein R4 and R5 are R45-1 and R6 and R7 are R67-1,
a compound wherein R4 and R5 are R45-1 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-2 and R6 and R7 are R67-1,
a compound wherein R4 and R5 are R45-2 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-3 and R6 and R7 are R67-1,
a compound wherein R4 and R5 are R45-3 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-4 and R6 and R7 are R67-1,
a compound wherein R4 and R5 are R45-4 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-5 and R6 and R7 are R67-1,
a compound wherein R4 and R5 are R45-5 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-6 and R6 and R7 are R67-1,
a compound wherein R4 and R5 are R45-6 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-7 and R6 and R7 are R67-1,
a compound wherein R4 and R5 are R45-7 and R6 and R7 are R67-2,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-2 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-3 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-4 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-5 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-6 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-7 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-8 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-9 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-10 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-11 and R9 and R10 are R910-11,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-1,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-2,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-3,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-4,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-5,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-6,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-7,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-8,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-9,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-10,
a compound wherein R8 and R11 are R811-12 and R9 and R10 are R910-11,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-3,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-4,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-5,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-6,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-7,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-8,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-9,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-10,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-11,
a compound wherein R4 and R5 are R45-1 and R8 and R11 are R811-12,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-3,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-4,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-5,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-6,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-7,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-8,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-9,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-10,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-11,
a compound wherein R4 and R5 are R45-2 and R8 and R11 are R811-12,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-1,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-2,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-3,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-4,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-5,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-6,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-7,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-8,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-9,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-10,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-11,
a compound wherein R4 and R5 are R45-3 and R8 and R11 are R811-12,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-1,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-2,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-3,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-4,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-5,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-6,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-7,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-8,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-9,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-10,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-11,
a compound wherein R4 and R5 are R45-4 and R8 and R11 are R811-12,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-1,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-2,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-3,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-4,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-5,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-6,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-7,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-8,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-9,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-10,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-11,
a compound wherein R4 and R5 are R45-5 and R8 and R11 are R811-12,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-1,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-2,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-3,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-4,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-5,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-6,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-7,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-8,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-9,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-10,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-11,
a compound wherein R4 and R5 are R45-6 and R8 and R11 are R811-12,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-1,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-2,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-3,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-4,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-5,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-6,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-7,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-8,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-9,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-10,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-11,
a compound wherein R4 and R5 are R45-7 and R8 and R11 are R811-12,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-2, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-4 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-7 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-10 and R9 and R10 are R910-8,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-3,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-4,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-5,
a compound wherein R4 and R5 are R45-4, R6 and R7 are R67-1, R8 and R11 are R811-12 and R9 and R10 are R910-8,
a compound described in [1] wherein Xxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94NR1xe2x80x94, or xe2x80x94S(O)pxe2x80x94 and C ring is an optionally substituted 5-membered heterocycle which contains one or two hetero atoms,
a compound wherein R4 and R5 are R45-4 and C ring is C-1,
a compound wherein R8 and R11 are R811-9, R9 and R10 are R910-7 and C ring is C-1,
a compound wherein R4 and R5 are R45-4 and C ring is C-2,
a compound wherein R8 and R11 are R811-9, R9 and R10 are R910-7 and C ring is C-2,
a compound wherein R4 and R5 are R45-4 and C ring is C-4,
a compound wherein R8 and R11 are R811-9, R9 and R10 are R910-7 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-3 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-3 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-3 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-3 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-3 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-3 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-4 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-4 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-4 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-4 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-4 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-4 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-8 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-8 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-8 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-8 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-8 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-8 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-10 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-10 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-10 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-10 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-10 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-10 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-11 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-11 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-11 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-11 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-11 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-11 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-12 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-12 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-12 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-12 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-12 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-12 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-13 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-13 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-13 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-13 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-13 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-13 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-14 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-14 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-14 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-14 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-14 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-14 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-15 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-15 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-15 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-15 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-15 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-15 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-16 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-16 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-16 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-16 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-16 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-16 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-18 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-18 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-18 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-18 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-18 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-18 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-19 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-19 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-19 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-19 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-19 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-19 and C ring is C-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4 R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R11 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6.
a compound wherein R4 and R5 are R45 1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-4, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-5, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-8, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-4, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-5, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17 and C ring is C-9,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-4,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R8 and R11 are R811-10, R9 and R10 are R910-7, X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20 and C ring is C-9,
a compound wherein Xxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94NR1xe2x80x94 or xe2x80x94S(O)p- and C ring is an optionally substituted 5-membered heterocycle which contains one or two hetero atoms,
a compound wherein C ring is pyridine ring, one of xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is 1-pyrolidinyl, 1-piperidinyl, 4-morphorinyl, 4-thiomorpholinyl, optionally substituted 1-piperadinyl (wherein the substituents are lower alkyl or lower alkenyl) or optionally substituted 1-pyrolyl (wherein the substituents are lower alkyl), and the other is xe2x80x94NHCH2CHxe2x95x90CMe2, xe2x80x94OCH2CHxe2x95x90CMe2 or xe2x80x94SCH2CHxe2x95x90CMe2,
a compound wherein C ring is pyridine ring, one of xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is 1-pyrolidinyl, optionally substituted 1-pyrolyl (wherein the substituents are lower alkyl), and the other is xe2x80x94NHCH2CHxe2x95x90CMe2, xe2x80x94OCH2CHxe2x95x90CMe2 or xe2x80x94SCH2CHxe2x95x90CMe2, salt or hydrate thereof.
Another embodiment of the present invention is
[2] a compound of the formula:

 
wherein each symbol is the same as defined in the above [1],
[3] a compound of the formula (Iaxe2x80x2):

 
wherein B ring is optionally substituted 5- or 6-membered heterocycle which contains one or two hetero atoms (wherein the substituent is halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkenyloxycarbonyl, optionally substituted lower alkylthio, optionally substituted lower alkenylthio, optionally substituted amino, guanidino, nitro, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyl or optionally substituted arylsulfonyloxy, excluding a compound wherein B ring is substituted with only halogen(s)) and W2 represents a bond when B ring is 5-membered heterocycle,
X, Xxe2x80x2, Y and Yxe2x80x2 are the same defined in [1],
R1, taken together with Y or Yxe2x80x2, may form xe2x80x94(CH2)m-, xe2x80x94(CH2)2xe2x80x94Qxe2x80x94(CH2)2xe2x80x94 (wherein Q is CH2, O, S or NRxe2x80x2), xe2x80x94CRxe2x80x2xe2x95x90CHxe2x80x94CHxe2x95x90CRxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94O(CH2)n-, xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94(CH2)nxe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94Nxe2x95x90CHxe2x80x94 wherein m is 4 or 5, n is 2 or 3,
Rxe2x80x2 is hydrogen, lower alkyl or lower alkenyl,
Y may be optionally substituted lower alkoxy when X is xe2x80x94CH2xe2x80x94,
Yxe2x80x2 may be optionally substituted lower alkoxy when Xxe2x80x2 is xe2x80x94CH2xe2x80x94,
Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94, Yxe2x80x2 may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when Xxe2x80x2 is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94,
Y may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or xe2x80x94NR1xe2x80x94,
Yxe2x80x2 may be hydrogen or halogen when Xxe2x80x2 is xe2x80x94CH2xe2x80x94 or xe2x80x94NR1xe2x80x94,
R4, R5, R6, R7, R12, R13, R14 and R15 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted alkenyloxy, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkenyloxycarbonyl, optionally substituted lower alkylthio, optionally substituted lower alkenylthio, optionally substituted amino, optionally substituted carbamoyl, guanidino, nitro, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyl or optionally substituted arylsulfonyloxy, excluding
(i) a compound wherein Y and Yxe2x80x2 are simultaneously hydrogen,
(ii) a compound wherein at least one of Y and Yxe2x80x2 is optionally substituted acyl,
(iii) a compound wherein at least one of xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is unsubstituted lower alkoxy, and
(iv) a compound wherein xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 are simultaneously optionally substituted lower alkoxy or amino substituted with phenyl,
salt or hydrate thereof.
The following compounds of (Iaxe2x80x2), salt or hydrate thereof are more preferable.
a compound wherein R4 and R5 are R45-1,
a compound wherein R4 and R5 are R45-2,
a compound wherein R4 and R5 are R45-3,
a compound wherein R4 and R5 are R45-4,
a compound wherein R4 and R5 are R45-5,
a compound wherein R4 and R5 are R45-6,
a compound wherein R4 and R5 are R45-7,
a compound wherein R6 and R7 are R67-1,
a compound wherein R6 and R7 are R67-2,
a compound wherein B ring is 5-or 6-membered heterocycle which contains at least one N atom (hereinafter referred to as xe2x80x9cB ring is B-1xe2x80x9d),
a compound wherein B ring is a 6-membered heterocycle which contains at least one N atom (hereinafter referred to as xe2x80x9cB ring is B-2xe2x80x9d),
a compound wherein B ring is optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyridazine or optionally substituted pyrazine (hereinafter referred to as xe2x80x9cB ring is B-3xe2x80x9d),
a compound wherein B ring is optionally substituted pyridine or optionally substituted pyrimidine (hereinafter referred to as xe2x80x9cB ring is B-4xe2x80x9d),
a compound wherein B ring is optionally substituted pyridine or optionally substituted pyrimidine (wherein the substituents are optionally substituted lower alkyl or optionally substituted lower alkoxy) (hereinafter referred to as xe2x80x9cB ring is B-5xe2x80x9d),
a compound wherein B ring is optionally substituted pyridine wherein xe2x80x9cB ring is B-6xe2x80x9d),
a compound wherein B ring is

 
xe2x80x83wherein G is CH or N, R8 and R11 are each independently halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted acyloxy, carboxy or optionally substituted lower alkoxycarbonyl (hereinafter referred to as xe2x80x9cB ring is B-7xe2x80x9d),
a compound wherein R12, R13, R14 and R15 are each independently hydrogen, hydroxy, halogen, optionally substituted lower alkoxy, optionally substituted acyloxy, optionally substituted lower alkylsulfonyloxy or optionally substituted arylsulfonyloxy (hereinafter referred to as xe2x80x9cR12, R13, R14, R15 and R16 are R12-15-1xe2x80x9d),
a compound wherein R12, R13, R14 and R15 are each independently hydrogen, hydroxy, halogen, lower alkoxy, acyloxy, optionally substituted lower alkylsulfonyloxy or arylsulfonyloxy (hereinafter referred to as xe2x80x9cR12, R13, R14 and R15 are R12-15-2xe2x80x9d),
a compound wherein R12, R13, R14 and R15 are each independently hydrogen, halogen or lower alkyl (hereinafter referred to as xe2x80x9cR12, R13, R14 and R15 are 12-15-3xe2x80x9d),
a compound wherein R12, R13, R14 and R15 are each independently hydrogen, chloro or fluoro (hereinafter referred to as xe2x80x9cR12, R13, R14 and R15 are R12-15-4xe2x80x9d),
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-1,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-2,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-3,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-4,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-5,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-6,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-7,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-8,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-9,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-10,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-11,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-12,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-13,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-14,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-15,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-16,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-17,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-18,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-19,
a compound wherein X, Y, Xxe2x80x2 and Yxe2x80x2 are XY-20,
a compound wherein R4 and R5 are R45-3 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-4 and R6 and R7 are R67-2,
a compound wherein R4 and R5 are R45-4 and B ring is B-1,
a compound wherein R4 and R5 are R45-4 and B ring is B-2,
a compound wherein R4 and R5 are R45-4 and B ring is B-4,
a compound wherein R4 and R5 are R45-4 and R12, R13, R14 and R15 are R12-15-3,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-1, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-4 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-2, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-5,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-7,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-3, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-3 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-5 and X, Xxe2x80x2, Y and Xxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-5 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-6,
a compound wherein R4 and R5 are R45-3, R6 and R7 are R67-1, R12, R13, R14 and R15 are R12-15-4, B ring is B-7 and X, Xxe2x80x2, Y and Yxe2x80x2 are XY-17,
a compound wherein B ring is B-7, X and Xxe2x80x2 are each independently xe2x80x94Oxe2x80x94, NR1xe2x80x94 (wherein R1 is hydrogen, lower alkyl, lower alkenyl or lower alkylcarbonyl) or xe2x80x94S(O)p- wherein p is an integer of 0-2,
Another embodiment of the present invention is
[4] a compounds of the formula (Ifxe2x80x2):

 
wherein one of B ring and C ring is optionally substituted 5- or 6-membered heterocycle which contains one or two hetero atoms and the other is 6-membered heterocycle which contains at least one N atom, excluding a compound wherein every substituent of B ring is selected from cyano and halogen,
X, Xxe2x80x2, Y, Xxe2x80x2 and W3 are the same as defined in [1] and W2 is the same as defined in [3],
R1, taken together with Y or Yxe2x80x2, may form xe2x80x94(CH2)m-, xe2x80x94(CH2)2xe2x80x94Qxe2x80x94(CH2)2xe2x80x94 (wherein Q is CH2, O, S or NRxe2x80x2), xe2x80x94CRxe2x80x2xe2x95x90CHxe2x80x94CHxe2x95x90CRxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94O(CH2)n-, xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94(CH2)n- or xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94Nxe2x95x90CHxe2x80x94 wherein m is 4 or 5, n is 2 or 3 and Rxe2x80x2 is hydrogen, lower alkyl or lower alkenyl,
Y may be optionally substituted lower alkoxy when X is xe2x80x94CH2xe2x80x94,
Yxe2x80x2 may be optionally substituted lower alkoxy when Xxe2x80x2 is xe2x80x94CH2xe2x80x94,
Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1,
Yxe2x80x2 may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or NR1xe2x80x94,
Y may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or NR1xe2x80x94,
Yxe2x80x2 may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or xe2x80x94NR1xe2x80x94,
R4, R5, R6 and R7 are the same as defined in [1],
salt or hydrate thereof. The following compounds among the compound (Ifxe2x80x2) are preferable.
a compound wherein B ring is B-2,
a compound wherein B ring is B-3,
a compound wherein B ring is B-4,
a compound wherein B ring is B-5,
a compound wherein B ring is B-6,
a compound wherein B ring is pyridine which may be substituted with lower alkyl or lower alkoxy,
a compound wherein C ring is C-1,
a compound wherein C ring is C-2,
a compound wherein C ring is optionally substituted morpholine ring, optionally substituted piperazine ring, optionally substituted imidazole ring, optionally substituted triazole ring or optionally substituted pyridine ring,
a compound wherein C ring is optionally substituted morpholine ring, optionally substituted piperazine ring, optionally substituted imidazole ring, optionally substituted triazole ring or optionally substituted pyridine ring (wherein the substituent is lower alkyl, aryl or lower alkenyloxy),
a compound wherein R4, R5, R6 and R7 are each independently hydrogen, hydroxy or lower alkylsulfonyloxy,
a compound wherein B ring is pyridine ring which may be substituted with lower alkyl or lower alkoxy, C ring is optionally substituted morpholine ring, optionally substituted piperazine ring, optionally substituted imidazole ring, optionally substituted triazole ring or optionally substituted pyridine ring (wherein the substituents are lower alkyl, aryl or lower alkenyloxy) and R4, R5, R6 and R7 are each independently hydrogen, hydroxy or lower alkylsulfonyloxy.
Another embodiment of the present invention is
[5] a compound of the formula (Igxe2x80x2):

 
wherein A ring and C ring are each independently optionally substituted 5- or 6-membered ring which contains one or two hetero atoms and W1 is a bond when A ring is 5-membered heterocycle,
X, Xxe2x80x2 Y and Yxe2x80x2 are the same as defined in [1],
R1, taken together with Y or Yxe2x80x2, may form xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)2xe2x80x94Qxe2x80x94(CH2)2xe2x80x94 (wherein Q is CH2, O, S or NRxe2x80x2), xe2x80x94CRxe2x80x2xe2x95x90CHxe2x80x94CHxe2x95x90CRxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94O(CH2)nxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94(CH2)nxe2x80x94 or C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94Nxe2x95x90CHxe2x80x94 wherein m is 4 or 5, n is 2 or 3 and Rxe2x80x2 is hydrogen, lower alkyl or lower alkenyl,
Y may be optionally substituted lower alkoxy when X is xe2x80x94CH2xe2x80x94,
Yxe2x80x2 may be optionally substituted lower alkoxy when Xxe2x80x2 is xe2x80x94CH2xe2x80x94,
Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or NR1,
Yxe2x80x2 may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when Xxe2x80x2 is xe2x80x94Oxe2x80x94 or NR1xe2x80x94,
Y may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or NR1,
Yxe2x80x2 may be hydrogen or halogen when Xxe2x80x2 is xe2x80x94CH2xe2x80x94 or NR1xe2x80x94,
R8, R9, R10 and R11 are the same as defined in [1] excluding a compound wherein all of R8, R9, R10 and R11 are selected from hydrogen and halogen,
salt or hydrate thereof. The following compounds among the compound (Igxe2x80x2) are preferable.
a compound wherein at least one of A ring and C ring is a 6-membered ring,
a compound wherein at least one of A ring and C ring is a 6-membered ring which contains N atom,
a compound wherein A ring is optionally substituted pyridine ring,
a compound wherein A ring is unsubstituted pyridine ring,
a compound wherein R8, R9, R10 and R11 are each independently hydrogen, lower alkyl or lower alkoxy,
a compound wherein C ring is optionally substituted pyridine ring, optionally substituted pyrimidine ring or optionally substituted pyrazine ring,
a compound wherein C ring is unsubstituted pyridine ring, unsubstituted pyrimidine ring or unsubstituted pyrazine ring,
a compound wherein xe2x80x94Xxe2x80x94Y is lower alkenyloxy or lower alkenylamino,
a compound wherein xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is amino which may be substituted with lower alkenyl,
a compound wherein A ring is unsubstituted pyridine ring, R8, R9, R10 and R11 are each independently hydrogen, lower alkyl or lower alkoxy, C ring is unsubstituted pyridine ring, unsubstituted pyrimidine ring or unsubstituted pyrazine ring, xe2x80x94Xxe2x80x94Y is lower alkenyloxy or lower alkenylamino and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is amino which may be substituted with lower alkenyl,
or salt or hydrate thereof.
Other preferable embodiments of the present invention are as follows.
[6] A pharmaceutical composition for use as an immunosuppressant comprising the compound of the formula (Ibxe2x80x2):

 
wherein C ring and W3 are the same as defined in [1],
X and Xxe2x80x2 are each independently xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR1xe2x80x94 (wherein R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl, lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl), xe2x80x94S(O)pxe2x80x94 (wherein p is an integer of 0-2) or a bond,
Y and Yxe2x80x2 are the same as defined in [1],
R1, taken together with Y or Yxe2x80x2, may form xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)xe2x80x94Qxe2x80x94(CH2)2xe2x80x94 (wherein Q is CH2, O, S or NRxe2x80x2), xe2x80x94CRxe2x80x2xe2x95x90CHxe2x80x94CHxe2x95x90CRxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94O(CH2)nxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94(CH2)nxe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94Nxe2x95x90CHxe2x80x94 wherein m is 4 or 5, n is 2 or 3 and Rxe2x80x2 is hydrogen, lower alkyl or lower alkenyl,
Y may be lower alkoxy when X is xe2x80x94CH2xe2x80x94,
Yxe2x80x2 may be lower alkoxy when Xxe2x80x2 is xe2x80x94CH2xe2x80x94,
Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or NR1xe2x80x94,
Yxe2x80x2 may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when Xxe2x80x2 is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94,
Y may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or xe2x80x94NR1xe2x80x94,
Yxe2x80x2 may be hydrogen or halogen when Xxe2x80x2 is xe2x80x94CH2xe2x80x94 or NR1,
Yxe2x80x2 may be hydrogen, hydroxy, halogen, nitro or oxo when Xxe2x80x2 is a bond, R4, R5, R6, R7, R8, R9, R10 and R11 are the same as defined in [1], excluding a compound wherein all of R8, R9, R10 and R11 are selected from hydrogen and halogen,
salt or hydrate thereof,
[7] a pharmaceutical composition for use as an immunosuppressant comprising the compound of the formula (Iaxe2x80x2):

 
wherein B ring is optionally substituted 5- or 6-membered heterocycle which contains one or two hetero atoms excluding a compound wherein every substituent of B ring is selected from cyano and halogen,
W2 is a bond when B ring is 5-membered heterocycle,
X, Xxe2x80x2, Y and Yxe2x80x2 are the same as defined in [3],
R1, taken together with Y or Yxe2x80x2, may form xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)2xe2x80x94Qxe2x80x94(CH2)2xe2x80x94 (wherein Q is CH2, O, S or NRxe2x80x2), xe2x80x94CRxe2x80x2xe2x95x90CHxe2x80x94CHxe2x95x90CRxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94O(CH2)nxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94(CH2)nxe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x2xe2x80x94Nxe2x95x90CHxe2x80x94 wherein m is 4 or 5, n is 2 or 3 and Rxe2x80x2 is hydrogen, lower alkyl or lower alkenyl,
Y may be optionally substituted lower alkoxy when X is xe2x80x94CH2xe2x80x94,
Yxe2x80x2 may be optionally substituted lower alkoxy when Xxe2x80x2 is xe2x80x94CH2xe2x80x94,
Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or NR1xe2x80x94,
Yxe2x80x2 may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when Xxe2x80x2 is xe2x80x94Oxe2x80x94 or NR1xe2x80x94,
Y may be hydrogen or halogen when X is xe2x80x94CH2xe2x80x94 or xe2x80x94NR1xe2x80x94,
Yxe2x80x2 may be hydrogen or halogen when.Xxe2x80x2 is xe2x80x94CH2xe2x80x94 or NR1,
R4, R5, R6, R7, R12, R13, R14 and R15 are the same as defined in [3], excluding
(i) a compound wherein xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 are simultaneously unsubstituted lower alkyl, optionally substituted lower alkoxy or unsubstituted acyloxy,
(ii) a compound wherein one of xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is methyl and the other is methoxy, and
(iii) a compound wherein xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is hydrogen or halogen and xe2x80x94Xxe2x80x94Y is unsubstituted lower alkyl, unsubstituted lower alkoxy or di(lower)alkylamino,
salt or hydrate thereof,
[8] a pharmaceutical composition for use as an immunosuppressant comprising the compound of the formula (Ifxe2x80x2), salt or hydrate thereof described in [4],
[9] a pharmaceutical composition for use as an immunosuppressant comprising the compound (Igxe2x80x2), salt or hydrate thereof described in [5],
[10] a pharmaceutical composition for use as an antiallergic agent comprising the compound of the formula (Ifxe2x80x2) described in [4], the compound of the formula (Igxe2x80x2) described in [5], the compound of the formula (Ibxe2x80x2) described in [6], the compound of the formula (Iaxe2x80x2) described in [7], salt, hydrate thereof,
[11] a pharmaceutical composition for use as a suppressant of the IgE production comprising the compound of the formula (Ifxe2x80x2) described in [4]the compound of the formula (Igxe2x80x2) described in [5], the compound of the formula (Ibxe2x80x2) described in [6], the compound of the formula (Iaxe2x80x2) described in [7], salt, or hydrate thereof,
[12] Use of the compound of the formula (Ifxe2x80x2) described in [4], the compound of the formula (Igxe2x80x2) described in [5], the compound of the formula (Ibxe2x80x2) described in [6], the compound of the formula (Iaxe2x80x2) described in [7], salt, or hydrate thereof for manufacturing a medicament for suppressing an immune response, treating and/or preventing allergic diseases,
[13] a method for suppressing an immune response or treating and/or preventing allergic diseases comprising administering the compound of the formula (Ifxe2x80x2) described in [4], the compound of the formula (Igxe2x80x2) described in [5]), the compound of the formula (Ibxe2x80x2) described in [6], the compound of the formula (Iaxe2x80x2) described in [7], salt, or hydrate thereof and
[14] a method for treating and/or preventing allergic diseases comprising administering the compound of the formula (Ifxe2x80x2) described in [4], the compound of the formula (Igxe2x80x2) described in [5], the compound of the formula (Ibxe2x80x2) described in [6], the compound of the formula (Iaxe2x80x2) described in [7], salt, or hydrate thereof.
The preferable compounds of the present invention are the ones of following structures. The symbols A2, A5, . . . B1, B4, . . . T1, T2 . . . in the tables means as follows.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Furthermore, the compounds having the above-mentioned structure wherein xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is one selected from a group of OCH2CHxe2x95x90CMe2, OCH2-2-furyl, OCH2-3-furyl, OCH2Cxe2x89xa1CMe, NHCH2CHxe2x95x90CMe2, N(iPr)SO2NHMe, NHCH(Me)CH2OMe, NHiPr, NH-iBu, NHc-Pent, NHCH2c-Hex, NHc-Hex, NHc-Hex-4-(xe2x95x90NOMe), NHcHex-4, 4-(OMe)2, NHCH2C6H4-4-B(OH)2, NHCH2C6H4-2-OH, NHCH2C6H3-3,4-(OH)2, NHCH2C6H2-3, 4, 5-(OMe)3, NHCH2C6H4-4-COOH, NHCH2C6H4-4-OH, NHCH2C6H4-3-OH, NHCH2-2-furyl, NHCH2-3-furyl, NH-4-tetrahydropyran, NHCH2-benzopyrrolyl, NHCH2-2-thiazolyl, NHCH2-quinolyl, NHcHex-4, 4-ethylenedioxy, 1-pyrolidinyl, 4-morpholinyl, 1-piperadinyl, 4-thiomorpholinyl, 1-piperidyl,

 
are preferable. The compounds wherein xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is xe2x80x94OCH2-2-furyl, xe2x80x94NHCH2CHxe2x95x90CMe2 or xe2x80x94OCH2CHxe2x95x90CMe2 are more preferable.
A process for producing the compound (I) is as follows.
A compound of the following formula (Ixe2x80x2) (hereinafter referred to as xe2x80x9ca compound (Ixe2x80x2)xe2x80x9d) can be produced by reacting a compound of the formula (IIa) (hereinafter referred to as xe2x80x9ca compound (IIa)xe2x80x9d) with a bicyclic compound of the formula (IIIa) (hereinafter referred to as xe2x80x9ca compound (IIIa)xe2x80x9d) or by reacting a compound of the formula (IIb) (hereinafter referred to as xe2x80x9ca compound (IIb)xe2x80x9d) with a bicyclic compound of the formula (IIIb) (hereinafter referred to as xe2x80x9ca compound (IIIb)xe2x80x9d).

 
wherein either of L and Z is dihydroxyborane, di(lower)alkyl borane or di(lower) alkoxyborane and the other is halogen or xe2x80x94OSO2(CqF2q+1) (q is an integer of 0 to 4) and other symbols are the same as defined above.
The compound (Ixe2x80x2) can be produced by reacting the compound (Ia) with the compound (IIIa) or by reacting the compound (IIb) with the compound (IIIb) in a mixture of an appropriate solvent such as benzene, toluene, N, N-dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, ethanol, methanol or the like and water or in an anhydrous solution in the presence of a palladium catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(OAc)2, PdCl2(CH3CN)2 or the like, preferably Pd(PPh3)4, under a basic condition (for example, by K3PO4, NaHCO3, NaOEt, Na2CO3, Et4NCl, Ba(OH)2, Cs2CO3, CsF, NaOH, Ag2CO3 or the like) at room temperature or with heating for several tens minutes to several tens hours.
One of substituents L and Z of the compounds to be reacted may be any of the borane groups which are applicable in the Suzuki Reaction (Chemical Communication 1979, 866, Journal of Synthetic Organic Chemistry, Japan, 1993, Vol.51, No.11, 91-100) and dihydroxyborane is preferable. The other may be any of the leaving groups which are applicable in the Suzuki Reaction, for example, halogen, xe2x80x94OSO2(CqF2q+1) wherein q is an integer of 0 to 4, or the like. Specifically, halogen, trifluoromethanesulfonyloxy (hereinafter referred to as OTf) or the like is preferable and bromine, iodine or OTf is more preferable.
The other substituents of A ring, B ring and C ring and xe2x80x94Xxe2x80x94Y of the compounds (IIa), (IIIa), (IIb) and (IIIb) may be any of the groups which do not affect the Suzuki Reaction, for example, any groups other than halogen and xe2x80x94OSO2(CqF2q+1) wherein q is an integer of 0 to 4.
For example, Y may be optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle which may be fused with benzene ring, Y may be optionally substituted lower alkoxy when X is xe2x80x94CH2xe2x80x94 and Y may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is xe2x80x94Oxe2x80x94 or xe2x80x94NR1xe2x80x94.
Even if any substituent of A ring, B ring or C ring is halogen, these reactions can be carried out without difficulty when the reactivity of the substituent L with the substituent Z is higher than that of halogen with either of substituents L and Z.
Even if either of substituents of A ring, B ring and C ring or xe2x80x94Xxe2x80x94Y is hydroxy, the above reactions can be preferably carried out. Preferably the above reactions may be carried out after the protection of hydroxy group with a usual hydroxy-protecting group such as methoxymethyl, benzyl, tert-butyldimethylsilyl, methanesulfonyl, p-toluenesulfonyl or the like, followed by deprotection by the usual methods.
As processes for producing the compound (Ixe2x80x2), the above mentioned Suzuki Reaction is most preferable in view of the efficiency and easiness but silicon, zinc, tin or the like can be used in place of the borane group in the above scheme.
For example, in the case that one of A and Z is xe2x80x94SiR173-r(Hal)r wherein R17 are independently lower alkyl, Hal is halogen and r is an integer of 1 to 3 and the other is halogen or xe2x80x94OSO2(CqF2q+1) wherein q is an integer of 0 to 4, the coupling reaction may be carried out using a usual palladium catalyst (Synlett (1991) 845-853, J. Org. Chem. 1996, 61, 7232-7233). Examples of preferable palladium catalysts are (i-Pr3P)2PdCl2, [(dcpe)PdCl2](dcpe=Cy2PCH2CH2PCy2), (xcex73-C3H5PdCl)2 and the like.
Even in the case that one of L and Z is xe2x80x94SnR183 wherein R18 are each independently lower alkyl and the other is halogen, acetyloxy or xe2x80x94OSO2(CqF2q+1) wherein q is an integer of 0 to 4, an objective compound can be obtained using a usual palladium catalyst (preferably Pd(PPh3)4 or the like) (Angew. Chem. Int. Ed. Engl. 25 (1986) 508-524).
In the case that one of L and Z is xe2x80x94Zn(Hal) wherein Hal is halogen and the other is halogen, an objective compound can be obtained (Acc, Chem. Res. 1982, 15, 340-348). Any usual palladium catalyst is applicable and Pd(PPh3)4, PdCl2(dppf), PdCl2(PPh3)2, PdCl2(P(o-Tolyl)3)2, Pd(OAc)2 and the like are exemplified as preferable examples.
All of these reactions may be carried out in a suitable solvent such as N,N-dimethylformamide, tetrahydrofuran or the like at room temperature or with heating for several tens minutes to several tens hours.
As compound (IIIa) and (IIIb) in the above reactions, may be used known compounds or compounds which are derived from a compound of the following formula (Va) (hereinafter referred to as xe2x80x9ca compound (Va)xe2x80x9d) or the following formula (Vb) (hereinafter referred to as xe2x80x9ca compound (Vb)xe2x80x9d) which can be produced by the known method or the following method.

 
wherein D is any of the groups which do not affect the Suzuki Reaction of L with Z, and may be the same group as L when a compound of the formula (IVb) is a bisymmetric compound. The other symbols are the same as above.
The compound (IIb) is reacted with the compound (IVa) or the compound (IIa) is reacted with (IVb) to give the compound (Va) or (Vb). When the compound (IVa) or (IVb) is not a bisymmetric compound, D is preferably a group which does not affect the Suzuki Reaction of L with Z and can be easily converted to L. For example, hydroxy, hydrogen, formyl, nitro or the like is preferable. In the reaction of L with Z, silicon, zinc, tin or the like can be used in place of the borane group as mentioned above.
D is converted into a group L which is applicable to the Suzuki Reaction.
A compound wherein D is hydroxy may be reacted with a trifluoromethanesulfonating agent such as trifluoromethanesulfonic anhydride, trifluoromethansulfonyl chloride, N-phenyltrifluorometbanesulfone imide or the like in a suitable solvent such as dichloromethane, chloroform, tetrahydrofuran or benzene in the presence of a base such as sodium hydride, pyridine, triethylamine, potassium carbonate or the like at xe2x88x9220xc2x0 C. or with heating for several minutes to several tens hours to give an objective compound wherein L is OTf.
For example, a compound wherein D is hydrogen may be reacted with a halogenating agent such as bromine, chlorine, iodine, N-bromosuccinimide or the like in a suitable solvent such as acetic acid, dichloromethane, chloroform, carbon tetrachloride, benzene, water or the like at xe2x88x9220xc2x0 C. or with heating for several minutes to several tens hours to give an objective compound wherein L is halogen.
A compound wherein D is formyl may be oxidated by the Baeyer-Villiger reaction to give a compound wherein D is formyloxy, followed by hydrolysis to give a compound wherein D is hydroxy. The compound wherein L is OTf can be obtained by the similar process as mentioned above.
A compound wherein D is nitro may be reduced to give a compound wherein D is amino, followed by the Sandmeyer Reaction to give a compound L is halogen.
A compound of the following formula (Ixe2x80x3) (hereinafter referred to as xe2x80x9ca compound (Ixe2x80x3)xe2x80x9d) can be produced by the Suzuki Reaction of a compound of the formula (VI) (hereinafter referred to as xe2x80x9ca compound (VI)xe2x80x9d) with a compound of the formula (IIa) (hereinafter referred to as xe2x80x9ca compound (IIa)xe2x80x9d) or by condensation of a compound of the formula (VII) (hereinafter referred to as xe2x80x9ca compound (VII)xe2x80x9d) with a compound of the formula (VIII) (hereinafter referred to as xe2x80x9ca compound (VIII)xe2x80x9d)

 
wherein either of M and Q is hydroxy or amino and the other is halogen, lower alkylsulfonyloxy, arylsulfonyloxy, lower alkylsulfonyl, arylsulfonyl or methyl having them as substituents, either of M and Q is lithium or Mg(Hal) wherein Hal is halogen and the other is carboxy, lower alkoxycarbonyl, carbamoyl or formyl, either of M and Q is formyl and the other is halogenomethyl, or either of M and Q is ethynyl and the other is halogen; and the other symbols are the same as defined above.
Various conditions for a reaction of the compound (VI) with the compound (IIa) are the same as those for the process for producing the compound (Ixe2x80x2).
In a reaction of the compound (VII) with a compound (VIII), when V2 of an objective compound is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94NHCH2xe2x80x94, either of M and Q is hydroxy or amino and the other is a leaving group such as halogen, lower alkylsulfonyloxy, arylsulfonyloxy, lower alkylsulfonyl, arylsulfonyl or the like or methyl having the leaving group as substituents. These two compounds are reacted in a suitable solvent such as benzene, toluene, acetone, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, pyridine, methanol, ethanol or the like in the presence of a base such as sodium hydride, pyridine, triethylamine, potassium carbonate, sodium hydroxide, potassium hydroxide or the like, if necessary by adding a copper catalyst such as copper powder, CuCl, CuO or the like at 0xc2x0 C. or with heating for several minutes to several tens hours to give the objective compound.
In a reaction of the compound (VII) with the compound (VIII), when V2 of an objective compound is xe2x80x94COxe2x80x94 or xe2x80x94CH(OH)xe2x80x94, either of M and Q is an organic metal such as lithium or Mg(Hal) wherein Hal is halogen and the other is carboxy, lower alkoxycarbonyl, carbamoyl or formyl. These two compounds are reacted in a suitable solvent such as diethylether, tetrahydrofuran, dimethoxyethan, dioxane or the like at xe2x88x9278xc2x0 C. to with heating for several minutes to several hours to give an objective compound.
When V2 of an objective compound is xe2x80x94CH(OR)xe2x80x94 wherein R is lower alkyl, after a compound wherein V2 is xe2x80x94CH(OH)xe2x80x94 is obtained, the obtained compound may be subjected to alkylation.
A compound wherein V2 is xe2x80x94COxe2x80x94 may be obtained by reacting a compound wherein V2 is xe2x80x94CH(OH)xe2x80x94 with an oxidizing agent such as chromic anhydride, Jone""s reagent or the like in a solvent such as t-butylalcohol, acetone or the like depending on the oxidizing agent at 0xc2x0 C. or with heating for several hours. A compound wherein V2 is xe2x80x94CH(OH)xe2x80x94 can be obtained also by reacting a compound wherein V2 is xe2x80x94COxe2x80x94 with an reducing agent such as sodium borohydride, aluminium lithium hydride or the like in a suitable solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, methanol, ethanol or the like.
When a compound wherein V2 of an objective compound is xe2x80x94CHxe2x95x90CHxe2x80x94, either of M and Q is formyl and the other is halogenomethyl (for example, halogen is chloro, bromo or iodo). An objective compound can be obtained by the Wittig Reaction (Organic Reaction, vol.14, p. 270, 1965).
When V2 of an objective compound is xe2x80x94CHxe2x89xa1CHxe2x80x94, either of M and Q is ethynyl and the other is halogen (preferably bromo or iodo). The objective compound can be synthesized by a coupling reaction with a generally used palladium catalyst (for example, Synthesis. (1980) 627, Tetrahedron, 1982, 38, 631).
Other substituents of A ring, B ring, C ring and xe2x80x94Xxe2x80x94Y of the compound (VI), (IIa), (VII) and (VIII) may be any substituent which does not affect the Suzuki Reaction of L with Z or a condensing reaction of M with Q. Even if in a reaction of the compound (VI) with the compound (IIa) wherein either of substituents is halogen, this reaction may be carried out without difficulty if the reactivity of a substituent L with a substituent Z is higher than the reactivity with halogen. Even if either of substituents is hydroxy, the above reaction can be carried out. Preferably hydroxy is previously protected, followed a deprotection after the above reaction.
As the compound (VI) in the above scheme, it may be used a known compound or a compound of the formula (X) which is synthesized in the following method.

 
wherein Dxe2x80x2 is a group which does not affect a condensing reaction of M with Q and when a compound of the formula (IX) is a symmetric compound, Dxe2x80x2 may be the same group as Q, and the other symbols are the same as defined above.
When the compound (IX) is not a symmetric compound, Dxe2x80x2 is preferably a group which does not affect the condensing reaction of M with Q and which can easily be converted to L. For example, hydrogen, formyl, protected hydroxy, nitro or the like is preferable. As a hydroxy-protecting group, exemplified are benzyl, t-butyldimethylsilyl, methoxymethyl and the like. A method for converting Dxe2x80x2 to L is similar to the above method for converting D to L. Other various conditions are similar to that for reacting the compound (VII) with the compound (VIII).
A known compound may be used as a compound (VIII) in the above reaction scheme and a compound synthesized by the usual method or derived from the above compound (Vb) by the usual method also may be used.
In the case that a compound has a substituent interfering of the above reaction, the substituent may be protected with a suitable protecting group in advance and the protecting group may be removed in a suitable step by the usual method. For example, if hydroxy interferes the reaction, it may be protected with methoxymethyl, methanesulfonyl, benzyl, trifluoromethanesulfonyl, tert-butyldimethylsilyl or the like, followed by deprotection in a suitable step.
For example, for a protection of hydroxy with methanesulfonyl, a compound which has hydroxy may be reacted with methanesulfonyl chloride in a solvent such as dichloromethane, chloroform, carbon tetrachloride or the like in the presence of a base such as triethylamine, pyridine or the like under ice-cooling or at room temperature for several hours. The protected compound may be deprotected with 1-4 N sodium hydroxide, potassium hydroxide, aqueous solution thereof, sodium methoxide, ethyl magnesium bromide or the like in a solvent such as dimethylsulfoxide, dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane or the like at room temperature or with heating for several tens minutes to several hours.
When methoxymethyl is used as a hydroxy-protecting group, a compound which has hydroxy may be reacted with chloromethylmethylether in a solvent such as tetrahydrofuran, dioxane, dimethoxyethane or the like in the presence of sodium hydride, diisopropylethylamine or the like to give a compound which has a protected hydroxy group. The compound may be subjected to a usual deprotection reaction with hydrochloric acid, sulfuric acid or the like in a solvent such as methanol, tetrahydrofuran, acetic acid or the like for a deprotection.
When tert-butyldimethylsilyl is used as a protecting group, a compound which has hydroxy may be reacted with tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl triflate or the like in a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, dimethylformamide, dichloromethane or the like in the presence of imidazole, triethylamine, 2,6-lutidine or the like. For a deprotection reaction the protected compound may be reacted with tetrabutylammonium fluoride or the like in a solvent such as tetrahydrofuran or the like.
A compound of the present invention thus obtained can be converted into a prodrug thereof. The term xe2x80x9cprodrugxe2x80x9d includes compounds which can easily be converted to the compound having the activity of the present invention in a living body. Any usual method for conversion into a prodrug may be used.
For example, hydroxy or amino which is attached to any possible position of a compound of the present invention may be substituted with a usual group for manufacturing a prodrug. For example, substituted acyl (wherein the substituent is carboxy, sulfo, amino, lower alkylamino or the like), phosphonoxy or the like may be introduced into the hydroxy, and substituted alkoxycarbonyl (wherein the substituent is halogen, acyloxy, hydroxyacyloxy, carboxyacyloxy, heterocyclylcarbonyloxy or the like) or substituted alkyl (wherein the substituent is aroylamino which may be substituted with acyloxy(lower)alkoxy or the like) may be introduced into the amino.
More definitely, when A ring or C ring has hydroxy as a substituent, a substituent such as xe2x80x94COCH2CH2COOH, xe2x80x94COCHxe2x95x90CHCOOH, xe2x80x94COCH2SO3H, xe2x80x94PO3H2, xe2x80x94COCH2NMe2, xe2x80x94CO-Py wherein Py is pyridine or the like may be introduced. When A ring or C ring has amino as a substituent(e.g., X, Xxe2x80x2 or the like), xe2x80x94COOCH2O(Cxe2x95x90O)CH2OH, xe2x80x94COOCH2O(Cxe2x95x90O)CH2CH2COOH, xe2x80x94COOCH2OAc, xe2x80x94COOCH(Me)OAc, xe2x80x94COOCH(Me)OCOCMe3, xe2x80x94COOCH2OCO(CH2)14Me, xe2x80x94COOCH2OCO-Pyr, xe2x80x94CH2NHCO-C6H4-o-OCH2OAc or the like may be introduced.
The immunosuppressant or anti-allergic agent of the present invention is useful for prevention or treatment of allergic diseases such as rejection symptom against transplantation of an organ or a tissue, graft-versus-host reaction caused by bone marrow transplantation, atopic allergic diseases (for example, bronchial asthma, allergic rhinitis, allergic dermatitis and the like), hypereosinophils syndrome, allergic conjunctivitis, systemic lupus erythematosus, polymyositis, dermatomyositis, scleriasis, MCTD, chronic rheumatoid arthritis, inflammatory bowel disease, injury caused by ischemia-reperfusion, pollenosis, allergic rhinitis, urticaria, psoriasis and the like.
A compound of the present invention can be administered orally or parenterally as a immunosuppressant, anti-allergic agent and/or suppressant on the IgE production. In the case of oral administration, it may be in any usual form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccal tablets, sublingual tablets and the like. When the compound is parenterally administered, any usual form is preferable, for example, injections (e.g., intravenous, intramuscular), suppositories, endermic agents, vapors and the like. Oral administration is particularly preferable.
A pharmaceutical composition may be manufactured by mixing an effective amount of a compound of the present invention with various pharmaceutical ingredients suitable for the administration form, such as excipients, binders, moistening agents, disintegrators, lubricants, diluents and the like. When the composition is of an injection, an active ingredient can be sterilized with a suitable carrier to give a pharmaceutical composition.
Specifically, examples of the excipients include lactose, saccharose, glucose, starch, calcium carbonate, crystalline cellulose and the like, examples of the binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone and the like, examples of the disintegrators include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar, sodium lauryl sulfate and the like, and examples of the lubricants include talc, magnesium stearate, macrogol and the like. Cacao oil, macrogol, methyl cellulose and the like may be used as base materials of suppositories. When the composition is manufactured as solutions, emulsified injections or suspended injections, dissolving accelerators, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents and the like may be added. For oral administration, sweetening agents, flavors and the like may be added.
Although the dosage of a compound of the present invention as an immunosuppressant, anti-allergic agent and/or suppressant on the IgE production should be determined in consideration of the patient""s age and body weight, the type and degree of diseases, the administration route or the like, a usual oral dosage for human adults is 0.05-100 mg/kg/day and preferable is 0.1-10 mg/kg/day. For parenteral administration, although the dosage highly varies with administration routes, a usual dosage is 0.005-10 mg/kg/day, preferably, 0.01-1 mg/kg/day. The dosage may be administered in one or several divisions per day.